1. Field of the Invention
This invention relates to a method, composition, and apparatus for relief of pain. More specifically, this invention relates to a method, composition, and apparatus for treating pain associated with wounds (surgical or nonsurgical) or inflamed/painful areas (e.g., cancer), as well as delivery systems and methods for delivering opioid analgesics directly to wounds (surgical or nonsurgical) or inflamed/painful areas (e.g., cancer). Delivery systems of some embodiments of the present invention preferably comprise those which can be intimately associated with a wound, including but not limited to, sutures, surgical staples, trocars, and implants, such as rods or pellets. Delivery systems of other embodiments of the present invention also may preferably comprise external wound dressings and wound closures including but not limited to, bandages, surgical dressings, gauzes, and sterile adhesive strips. The delivery systems allow for the delivery of opioids and/or other narcotic analgesics to the site of the wound over an extended period of time.
2. Background of the Invention and Related Art
Morphine is the prototype of the class of opioid analgesics which can exert a centrally-mediated analgesic effect by activating opioid receptors within the brain. Morphine has been used for centuries and is unsurpassed as an analgesic for severe pain. However, morphine has a number of serious side effects which hamper its widespread use and acceptance by physicians and patients. Morphine's side effects (and/or side effects of other opioid analgesic agents) include addiction, nausea, respiratory depression, somnolence, and dysphoria, all of which are mediated by morphine's action within the central nervous system. In addition, the development of tolerance and physical dependence with repeated use is a characteristic side effect of all opioid drugs. Major research efforts have been directed toward development of morphine-like drugs that act within the brain and are devoid of the undesirable side effects but that retain the desirable potent analgesic effects. However, these efforts have been relatively unsuccessful and there has been continuing need for improvement.
Conventional therapy for pain (surgical and nonsurgical) includes the use of oral, intramuscular, intravenous, epidural, and intrathecal morphine which travels through the bloodstream to reach opioid receptors in the brain, or interacts with opioid receptors directly in the central nervous system. The side effects described in the literature (including death) are almost completely attributable to these drugs' actions in the central nervous system.
Due to severe postoperative pain, many patients will have an extended stay in the hospital solely for control of the severe pain. Consequently, patients often receive significant amounts of opioids intravenously or intramuscularly, which can often result in side effects which include respiratory depression, nausea, vomiting, dysphoria, and a significant decrease in blood pressure. The side effects often necessitate the concomitant use of other medications just to control them. Furthermore, a prolonged stay in the hospital can increase the infection rate due to a high incidence of resistant pathogens in the hospital.
In contrast, patients who have adequate pain control without side effects can leave the hospital sooner and recover at home. The economic implications for the health care system are a decreased incidence of nosocomial infections as well as side effects and consequently a significant reduction in the cost of surgery.
Because of their potent centrally-mediated (brain and spinal cord) analgesic effects, intravenous administration of opioids has remained the route of choice. However, none of the conventional routes of administration has provided an acceptable system for delivering optimally effective levels of an analgesic substance without the detrimental side effects. In addition, it appears that optimal release of those medications has also not been established. It would, therefore, be desirable to derive the analgesic benefits of this class of opioids without the detrimental side effects that are primarily attributable to its actions within the brain.
In addition to their presence in the brain, opioid receptors have been found on sensory nerves in inflamed subcutaneous tissue. This finding was reported in Stein et al., "Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat," Neurosci. Lett. 84:225-228 (1988), and in Stein et al., "Antinociceptive effects of mu- and kappa-agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism of action," Eur. J. Pharmacol. 155:255-264 (1988). Small doses of opioids, when applied locally or topically in inflamed areas outside the central nervous system, can produce local analgesic effects by interacting with the opioid receptors on peripheral sensory nerves and producing local analgesia. This finding was discussed in Stein et al., "Opioids as novel intra-articular agents in arthritis," In: Progress in Pain Research and Management, Fields, H. L., and Liebeskind, J. C., eds., 1:289-296, IASP Press, Seattle, (1994).
Peripheral opioid effects are not initially apparent in normal tissue, but do become apparent within minutes to hours at the site of inflammation. It is believed that the reason for the pain relief is that opioids can gain easier access to neuronal opioid receptors during inflammation as a result of the disruption of the perineurium (which is normally an impermeable sheath encasing the peripheral nerve fiber). Further, the number of peripheral sensory nerve terminals is increased in inflamed tissue and a phenomenon known as sprouting occurs in which the number of fibers increases significantly within inflamed tissue. The sprouting results in a subsequent increase in the number of morphine receptors that are peripherally accessible to locally-applied opioids.
The peripheral opioid effects are observed to be much more pronounced in inflamed than non-inflamed tissue, and this constitutes an advantage according to the present invention since inflammation is associated with surgery. In addition, it has been determined that small doses of conventional opioid drugs such as morphine, or other opioids, can produce potent analgesic effects after local application to inflamed tissues.
In accordance with the present invention, it has been determined that opioid receptors can be directly targeted in peripheral tissue (local analgesia) rather than dosing to affect opioid receptors in the brain. Importantly, the doses of an opioid analgesic required to produce analgesia in the periphery (local analgesia) are extremely small and, therefore, are substantially devoid of the above-mentioned, centrally-mediated side effects.
The topical application of opioids for the treatment of pain is disclosed in U.S. Pat. No. 5,589,480, to ELKHOURY et al., the entire contents of which are hereby incorporated by reference as though set forth in full herein. ELKHOURY et al. discloses the topical application of opioids in vehicles which do not promote the transdermal migration of the drug. ELKHOURY et al. discloses the treatment of external skin lesions and burns by such treatment. ELKHOURY et al. also discloses the use of such a formulation on mucosal membranes, including those of the mouth and throat. A clinical demonstration of such application is presented in "Analgesic Effect of Topical Opioids on Painful Skin Ulcers," by Back et al., in Letters to the Editor, Journal of Pain and Symptom Management, Vol. 10, No. 7, October 1995, wherein it was shown that diamorphine applied in an occlusive wound dressing could relieve the pain associated with decubitus ulcers and malignant skin ulcerations.
Although the topical application of opioids, as described in ELKHOURY et al., is appropriate for the aforementioned ailments, such as skin lesions and burns, topical application would likely be ineffective for surgical and other wounds. Wounds, by their nature, are in intimate contact with the blood stream and blood supply. Plasma and blood fluids are critical to the wound healing process as they supply the necessary materials, including blood cells as well as different factors involved in the complex reparative mechanism. Blood brings oxygen and growth factors and removes anoxic and damaged materials. In addition, it would likely absorb any locally applied opioid after only a short period of time, thereby rendering it ineffective.
A surgical incision comprises several layers: skin, fat, fascia, muscle, connective tissue, etc. Often, each layer requires suturing for wound closure. The pain associated with surgical wounds often emanates not only from the surface skin incision, but from a deeper layer (muscle and connective tissue). These deep layers result in significant post-surgical pain. In fact, surgical trauma to muscle and fascia is the primary source of post-surgical pain. An opioid analgesic preparation, in accordance with ELKHOURY et al., applied to deep layers prior to wound closure would be expected to be rapidly cleared from the area, providing only short-term pain relief, if any.
The present invention addresses the problems posed in the aforementioned case by providing a device and/or method whereby an analgesic may be delivered to the origin of pain over an extended period of time. The present invention, in the form of surgical sutures, pellets, staples, etc., can be placed even at the deepest of incisions or even at the skin, providing excellent relief of pain resulting from skin or deep wounds (surgical or nonsurgical). The present invention, in the embodiment of a suture or staple with an opioid analgesic incorporated or impregnated therein, could be used to close surgical wounds. The analgesic agent may be incorporated into a polymeric material, of which the suture, pellet, or staple is made. Alternatively, the opioid analgesic agent may be incorporated into a suture material which is not absorbable, such as nylon. In either embodiment, the opioid analgesic agent is released from the suture in minimal amounts and over an extended period of time, providing relief of pain. Similarly, pellets of an absorbable material, with an opioid analgesic incorporated therein, could be sprinkled into a wound at different layers prior to closure. The present invention provides an apparatus and method whereby an analgesic may be delivered to a local area, without significant systemic absorption, and thereby providing local analgesia.
The medical field contains examples of devices which deliver medicaments to a body. Examples include drug-containing sutures, staples, pellets, and the like. U.S. Pat. No. 3,991,766, to SCHMITT et al., discloses the use of a polyglycolic acid polymer in surgical sutures, clips, and storage pellets, which can be used alone or with a medicament contained within. Acceptable medicament classes listed by SCHMITT include antibiotics, antiseptics, anesthetics, antioxidants, as well as steroid hormones. Similarly, U.S. Pat. No. 5,019,096, to FOX et al., discloses matrix-forming polymers which contain antimicrobial agents. Fibrous articles, including threads, or intrauterine devices, which are used to deliver povidone iodine, are disclosed in U.S. Pat. No. 4,582,052, to DUNN et al. U.S. Pat. No. 4,024,871, to STEPHENSON, discloses sutures which are impregnated with an antibiotic. U.S. Pat. No. 4,764,377, to GOODSON, discloses implants impregnated with antibiotics, and which are to be used in periodontal disease. Other implants which can be used to deliver drugs subdermally are disclosed in U.S. Pat. No. 5,366,081, to KAPLAN et al., and in U.S. Pat. No. 5,282,829, to HERMES. For their disclosure of the manner and process for making surgical devices, including sutures and implants, the contents of SCHMITT (U.S. Pat. No. 3,991,766), FOX (U.S. Pat. No. 5,019,096), DUNN (U.S. Pat. No. 4,582,052), STEPHENSON (U.S. Pat. No. 4,024,871), GOODSON (U.S. Pat. No. 4,764,377), KAPLAN (U.S. Pat. No. 5,366,081), and HERMES (U.S. Pat. No. 5,282,829) are hereby incorporated by reference as though set forth in full herein.
Opioid drugs are characterized not only by their analgesic properties, but also by their ability to cause physical dependence and tolerance through a centrally-mediated mechanism. Tolerance results in a need to increase the dose necessary to produce centrally-mediated analgesia. Because of the need to increase the dose, an implantable drug depot device delivering an opioid in a centrally-effective dose would quickly become ineffective in its ability to produce analgesia. For this reason, implantable extended-release opioid delivery devices, while available, are not very useful.
Based on several published studies, strong evidence now exists demonstrating that opioid receptors are present in areas of inflamed tissue. Analgesia has been reported with morphine injections into a closed space, such as in the knee of arthritic patients. See, as examples of such studies, Khoury et al., Anesthes. 77: 263-266 (1992); Stein et al., N. Engl. J. Med., 325:1123-1126 (1991); and Basbaum, et al., N. Engl. J. Med., 325: 1168-1169 (1991). However, such practice is relatively restricted by the fact that the treatment generally requires administration by a qualified physician. In addition, for continued relief, repeated injections are necessary.
Like the pain emanating from an afflicted joint in arthritis, the pain associated with a wound is significant and debilitating. Frequently, hospital stays following surgery are extended because the surgical patient continues to require the administration of significant amounts of an opioid analgesic agent for relief of the severe pain. Extended stays, in turn, result in greatly increased medical bills.
A feature unique to the treatment of localized pain is the minimal amount of opioid analgesic agent required to bring about local analgesia. Apparently, the inflamed area in the locality of the pain exhibits an increased sensitivity to the antinociceptive effects of opioid analgesic agents, possibly because of activation of peripheral opioid receptors located on primary afferent neurons. The activation may occur via several means: de novo synthesis of opioid receptors, resulting in an increase in the total number of opioid receptors in the area; axonal transport of pre-existing opioid receptors to the nerve terminal, similarly increasing the total number of opioid receptors in the area; some other process of activating pre-existing opioid receptors by the inflammatory process. A discussion of such mechanisms is presented in Stein, "Peripheral and non-neuronal opioid effects," Curr. Opin. Anaesth. 7:347-351 (1994).
Regardless of the mechanism by which opioid sensitivity is increased, methods are known by which pain can be modulated at peripheral sites. However, such existing treatments, including intra-articular administration of opioid analgesic agents, are limited by the fact that treatments must be applied frequently, because the opioid analgesic effect commonly has a duration of only 8 hours after injection. Even a long-lasting opioid, such as methadone, is usually only effective for less than 24 hours. Prolonged pain relief following surgery has been demonstrated, but such relief is often provided by routes of administration including targeting central nervous system receptors. Specifically, an article published in Connecticut Medicine, (Vol. 60, No. 3, March, 1996), and authored by Charles Needham, shows prolonged relief of pain following lumbar surgery. The Needham article discloses the use of a morphine nerve paste applied to the dura in the epidural space (central nervous system) and nerve roots to relieve post-surgical pain. Pain relief from the morphine applied in the epidural space (centrally-mediated) is very likely an important component of the analgesic effect demonstrated by Needham. However, the author indicates that peripheral opioid receptors could also be involved in the resulting postoperative pain relief.
The present invention addresses the foregoing problem, that is, the present invention provides a method whereby peripheral opioid receptors may be targeted, and whereby repeated administration is not necessary. The present invention provides a level of relief of the deep pain associated with trauma, as well as other conditions (e.g., cancer) that is quite unexpected. Because of the ability of the present invention to deliver the analgesic directly to the pain receptors at the site of the wound, a lower than normal dose of analgesic is needed. In fact, the present invention delivers doses that are too low to produce analgesia in a centrally-mediated manner. The use of a lower dose avoids all of the detrimental centrally-mediated side effects associated with systemic administration of the analgesic. Consequently, the present invention is a breakthrough in the field of relief of surgical pain and other pains.